Psychosedaticompositions containing 1-acyl-5-phenyl-1h-1,5-benzodiazepine-2,4-(3h, 5h)-diones and methods of using the same

ABSTRACT

WHEREIN R1 is hydrogen, straight-chain alkyl of one to 15 carbon atoms, chloromethyl, trifluoromethyl, methylamino, ethoxy, cyclohexyl, phenyl, chlorophenyl, dichlorophenyl, tolyl, dimethoxyphenyl, nitrophenyl, benzyl, styryl, thienyl or furyl, R2 is hydrogen, methyl, chlorine or methoxy, and R3 is hydrogen, 7-chloro, 7-bromo, 8-methyl, 7-trifluoromethyl or 8-trifluoromethyl, AND METHODS OF USING SAID COMPOSITIONS AS PSYCHOSEDATIVES, MUSCLE-RELAXANTS AND ANTICONVULSIVES.   Pharmaceutical compositions containing as an active ingredient a compound of the formula

United States Patent Weber et a1.

[54] PSYCHOSEDATICOMPOSITIONS CONTAINING l-ACYL-S-PHENYL-lI-I-1,S-BENZODIAZEPINE-2,4-(3H, 5H): DIONES AND METHODS OF USING THE SAME[72] Inventors: Karl-Heinz Weber, Gau-Algesheim; Karl Zeile, Ingelheim(Rhine); Roll Giesemann, Bingen (Rhine); Peter B. Danneberg,QFQEQEPEMQQ? Germany [22] Filed: March 25, 1971 [21] Appl. No.: 128,173

Related US. Application Data [63] Continuation-impart of Ser. No.819,940, April 28, 1969, Pat. No. 3,624,076.

[30] Foreign Application Priority Data April 29, 1968 Austria ..A4165/68 [52] US. Cl. ..424/244, 424/275, 424/285 [51] Int. Cl. ..A6lk27/00 [58] Field of Search ..424/244 [5 6] References Cited OTHERPUBLICATIONS Buchi et al., Hehr. Chim. Acta Vol. 39, pp. 957 965 (1956).

[ Aug. 8, 1972 Primary Examiner -stanley J. Friedman Attorney-Hammond &Littell s71 ABSTRACT Pharmaceutical compositions containing as an activeingredient a compound of the formula .35... wherein R is hydrogen,straight-chain alkyl of one to 15 car bon atoms, chloromethyl,trifluoromethyl, methylamino, ethoxy, cyclohexyl, phenyl,

10 Claims, No Drawings wherein R is hydrogen, straight-chain alkyl ofone to carbon atoms, chloromethyl, trifluoromethyl, methylamino, ethoxy,cyclohexyl, phenyl,

chlorophenyl, dichlorophenyl, tolyl, dimethoxyphenyl, nitrophenyl,benzyl, styryl, thienyl or furyl,

R is hydrogen, methyl, chlorine or methoxy, and

R; is hydrogen, 7-chloro, 7-bromo, 8-methyl, 7-

trifluoromethyl or S-trifluoromethyl.

The compounds embraced by Formula I above may be prepared by acylationof a compound of the formula wherein R and R have the same meanings asin Formula I and X is hydrogen or an alkali metal, in the l-position.The acylation may be effected with a common acylating agent, such as anacid halide, an acid anhydride or an isocyanate, pursuant to customarymethods and under reaction conditions which are usually applied toacylation reactions.

The starting compounds of the Formula II, in turn, may be prepared asdescribed in copending application Ser. No. 703,188, filed Feb. 5, 1968,that is, by cyclization of an N-phenyl-N-(2-aminophenyl)-malonic acidalkyl ester amide of the formula wherein R is lower alkyl and R and Rhave the same meanings as in Formula I. The hydrolysis and ring closureproceed smoothly and with good yields in an acid as well as an alkalinemedium, preferably in the presence of an alcoholic or aqueous alcoholicsolvent; however, other inert solvents such as tetrahydrofuran ordioxane, are also suitable; for acid cyclization, acetonitrile may alsobe used as the solvent. Mineral acids, and particularly hydrohalicacids, such as hydrochloric acid, hydrobromic acid, hydroiodic acid,sulfuric acid, phosphoric acid and perchloric acid are preferably usedas acid cyclization agents. Examples of alkaline cyclization agents aresodium alcoholates and alkali metal hydroxides.

The reaction periods depend upon the quantity of acid or alkali employedand'upon the type of solvent used; they vary between several hours andseveral days.

.The reaction temperatures are preferably between +20C and the boilingpoint of the solvent which is used.

Examples of compounds of the Formula I which may be obtained bythe-above-described method are the following: 7-chlorol-formyl-5-phenyll H- l ,S-benzodiazepine- 2,4-[3H,5H]-dione,l-acetyl-7-chloro-5-phenyl-1H-l,5-benzodiazepine- 2,4-[3H,5H]-dione,7-chloro-5 -phenyll -propionyl-l H- l ,5-benzodiazepine-2,4-[3H,5H]-dione,7-chloro-l-chloroacetyl-5-phenyl-lH,-1,5- benzodiazepine-2,4-[ 3H,5 H]-dione, 7-chloro-5-phenyll -trifluoroacetyll H- l ,5-

' benzodiazepine-2,4-[3H,5H]-dione,

7-chlorol -cyclohexyl-carbonyl-5phenyll H-l ,5- benzodiaze-pine-2,4-[ 3H,5H I-dione, l-benzoyl-7-chloro-5-phenyll H,-] ,S-benzodiazepine- 2,4-[3H,5H l-dione,

l-benzoyl-7-bromo-5-phenyll H,-l ,S-benzodiazepine- 2,4-[3H,5H]-dione,l-benzoyl-8-methyl-5-phenyl-l H l ,S-benzodiazepine- 2,4-[ 3H,5Hl-dione,

l-benzoyl-5-( p-methoxyphenyl 1 PM ,5- benzodiazepine-2,4-[3H,5Hl-dione, l-benzoyl-S-phenyl-8-trifluoromethyl-l H-1 ,5-benzodiazepine-2,4-[3H,5H]-dione, l-benzoyI-7-chloro-5-(p-methylphenyl)-l H- l ,5- benzodiazepine-2,4-[ 3H,5H ]-dione, 1benzoyl-7-chloro5-(p-chlorophenyl )-l H-l ,5- benzodiazepine-2,4-[3H,5I-I]-dione,l-benzoyl-5-phenyl-7-trifluoromethyl-l H-1 ,5-benzodiazepine-2,4-[3H,5H]-di0ne, 7-chlorol -(o-methylbenzoyl)-5-phenyll H- l ,5- benzodiazepine-2,4-[3H,5H]-dione, 7-chlorol-(p-methylbenzoyl )-5-phenyll H- l ,5-

benzodiazepine-2,4-[3H,5Hl-dione, 7-chlorol o-fluorobenzoyl )--phenyl-lH-l ,5- benzodiazepine-2,4-[3H,5Hl-dione, 7-chlorol-(p-nitrobenzoyl)-5-phenyl-l H,-l ,5- benzodiazepine-2,4-[3H,5Hl-dione,7-chloro-l-(3,4-dimethoxybenzoyl)-5-phenyl-1H,-1,5-benzo-diazepine-2,4-[ 3H,5H ]-dione,'7-chloro-l-(2,4-dichlorobenzoyl)-5-phenyl-lH-l,5'benzo-diazepine-2,4-l3H,5Hl-dione, 7-chloro-5-phenyll -phenylacetyll H-l,5- benzodiazepine-2,4-[3H,5H]-dione, 7-chlorol -cinnamyl-5-phenyl-l H-l,S-benzodiazepine- 2,4-[3l-l,5H]-dione, 7-chlorol -furoyl-5-phenyll H- 1,S-benzodiazepine- 2,4-[3H,5H]-dione, 7-chloro-5-phenyll -thenoyl-l H- 1,5-benzodiazepine- 2,4-[3H,5H]-dione,l-ethoxycarbonyl-7-chloro-5-phenyll H-1 ,5-benzodiazepine-2,4-[3H,5H]-dione,7-chloro-l-methylcarbamoyl-5-phenyl-lH-1,5-benzodiazepine-2,4-[3H,5H]-dione,7-chloro-l-lauroyl-S-phenyl-lH-l,5-benzodiazepine- 2,4-[3H,5H]-dione,7-chlorol -palmitoyl-5-phenyll H- l ,5- benzodiazepine-2,4-[3H,5H]-dione and l-benzoyl-5-phenyl-7-trifluoromethyl-l H- l ,5-benzodiazepine-2,4-[3H,5H]-dione.

The following examples further illustrate the preparation of compoundsof the Formula I and will enable others skilled in the art to understandit more completely.

EXAMPLE 1 l-benzoyl-7-chloro-5-phenyll H-1 ,5-benzodiazepine-2,4-[3H,5H]-dione 0.5 mol (154 gm) of the sodium salt of7-chloro-5- phenyl- 1 H-l ,5-benzodiazepine-2,4-[3H,5H ]-dione weredissolved in 2 liters of tetrahydrofuran, and the solution was admixedat room temperature with 60 ml of benzoylchloride. The mixture wasrefluxed for three hours, then evaporated, and the residue was taken upin methylenechloride. Undissolved starting material was vacuum filteredoff, and the filtrate was extracted with 300 to 500 ml of cold water.The methylenechloride phase was dried with anhydrous magnesium sulfateand evaporated, and the residue was recrystallized twice from toluene.One hundred and ten gm (55 percent of theory) ofl-benzoyl-7-chloro-5-phenyl-l H-1 ,5- benzodiazepine-2,4-[3H,5Hl-dione,m.p. 208-209C, of the formula were obtained. The starting material wasprepared as follows: 23 gm of sodium were dissolved in 2,3 liters ofabsolute alcohol, and 230 gm of N-(2-amino-5-chlorophenyl)-N-phenyl-malonic acid ethyl ester amide were added to thesolution. After five hours stirring at room temperature, theprecipitated sodium salt wasvacuum-filtered off, washed with coldalcohol and ether, and dried at l20C. Yield: 200 gm (93 percent oftheory).

EXAMPLE 2 l-benzoyl-7-chloro-5-p henyll H-l ,5-benzodiazepine-2,4-[3H,5Hl-dione 0.5 mol (143 gm) of7-chloro-5-phenyl-lH-l ,5- benzo-diazepine-2,4-[ 3H,5H l-dione weresuspended in 2.5 liters of dry tetrahydrofuran and, after addition of 24gm of a 50 percent sodium hydride suspension in mineral oil, the mixturewas stirred at room temperature until everything had dissolvedcompletely (about 1 hour). Thereafter, 122 gm of benzoic acid anhydridewere added to the solution, and the mixture was refluxed for l0 minutes.The reaction mixture was worked up as described in Example 1, and theraw product was recrystallized from toluene. Fifty gm (25 percent oftheory) of 1-benzoyl-7-chloro-5-phenyl-lH-l,5-benzodiazepine-2,4-[3H,5H]-dione, m.p. 208-209 C, were obtained.

EXAMPLE 3 7-chloro-5-phenyll -propionyll H- l ,5-benzodiazepine-2,4-[3H,5H]-dione 0.1 mol (28.6 gm) of7-chloro-5-phenyl-lH-l ,5- benzodiazepine-2,4-[3H,5H]-dione weresuspended in 750 ml of absolute tetrahydrofuran, and the suspension wasstirred with 5 gm of a 50 percent sodium hydride suspension in mineraloil for 2 hours at room temperature. After everything had dissolved, l3gm of propionic acid anhydride were added, the mixture was first stirredfor 2 hours at room temperature and then refluxed. After evaporation ofthe reaction solution in vacuo, the residue was taken up in methylenechloride, the insoluble matter was vacuum-filtered off, and the filtratewas washed with water, and evaporated, and the residue wasrecrystallized from toluene. Twenty nine gm (90 percent of theory) of7-chloro-5-phenyl-lpropionyll H-l ,5-benzodiazepine-2,4-[3H,5H]-dione,m.p. l94-196C, of the formula were obtained] EXAMPLE 47-chloro-5-phenyl-l -propionyll H- l ,5-benzodiazepine-2,4-[3H,5H]-dione 0.1 mol (28.6 gm) of7-chloro-5-phenyl-lH-l,5- benzodiazepine-[3H,5H ]-dione were refluxedwith 200 ml of pyridine and 18 gm of propionic acid anhydride for 22hours. Thereafter, the solution was evaporated in vacuo, and the rawproduct was worked up as described in Example 1. Yield: 25.8 gm percentof theory), m.p. l94-l96C.

EXAMPLE 5 7-chloro-5-phenyl-l -propionyll H-l ,5-

benzodiazepine-2,4-[3H,5H]-dione 0.1 mol (28.6 gm) of7-chloro-5-phenyl-lH-l,5- benzodiazepine-2,4-[3H,5H]-dione were refluxedwith 300 ml of propionic acid anhydride for 15 hours. Subsequently, thereaction solution was evaporated in vacuo, the residue was taken up inmethylenechloride, and the reaction product was isolated as described inExample I. Yield: 25.8 gm (80 percent of theory), m.p. l94196C.

EXAMPLE 6 7-chlorol -methylcarbamoyl-5-phenyl-l H-l ,5-benzodiazepine-2,4[3H,5H]-dione 0.1 mol (28.6 gm) of7-chloro-5-phenyl-lH-l,5- benzodiazepine-2,4-[3H,5H]-dione were stirredwith 850 ml of absolute dioxane, 30 ml of methylisocyanate and 1.5 ml oftriethylamine for 15 hours at 40C. Thereafter, the reaction solution wasevaporated in vacuo, water was added to the residue, the crystals formedthereby were vacuum-filtered off, and the filter cake was recrystallizedfrom methylenechloride/diisopropylether. Thirty gm (89 percent oftheory) of 7-chloro-l-methylcarbamoyl-S- phenyll H- l,5-benzodiazepine-2,4-[ 3H ,5H ]-dione,

m.p. 306308C, ofthe formula NHCH; .023 N i N c I ll 0 were obtained.

EXAMPLE 7 7-chloro-5-phenyll -propionyll H- l ,5-benzodiazepine-2,4-[3H,5H]-di0ne 0.1 mol (28.6 gm) of7-chloro-5-phenyl-lH-l,5- benzodiazepine-2,4-[3H,5H]-dione were refluxedwith 20 gm of propionic acid anhydride in 480 ml of xylene for 72 hours.The reaction solution was allowed to cool and was then vacuum filtered;20 gm of the starting material were recovered as the filter cake. Byevaporating the filtrate 6 gm (19 percent of theory) of the reactionproduct, m.p. l94l 96C, were isolated.

Using a procedure analogous to that described in the preceding examples,the following additional compounds of the Formula 1 above were prepared:

benzodiazepine-2,4-[3H,5H]-dione, m.p. l87'l 88C, of the formula from7-chloro-5-phenyl-l H-l ,5-benzodiazepine-2,4-[ 3H ,5H l-dione andethoxycarbo'nyl chloride.

EXAMPLE 9 7-chloro -5-ph enyll -formyll H-l ,S-benzodiazepine- 2,4-[3H,5H l-dione, m.p. 210-21 1C, ofthe formula from 7-chloro-5-phenyl- 1PH ,5-benzodiazepine-2,4-[ 3H,5H]'dione and formyl chloride.

EXAMPLE l0 7-chloro-5-phenyll -(o-chloroben zyl l H- l ,5-benzodiazepine-2,4-[3H,5H]-dione, m.p. 222224C, of the formula 3H ,5H]-dione and o-chloro-benzoyl chloride.

EXAMPLE 1 l 7chloro-5-phenyl-l-(o-methyl-benzoyl)-1H-1,5-benzodiazepine-2,4-[3H,5Hl-dione, m.p. l97200C,

of the formula --CHa 0: I 0 N L 0 /c Hz from 7-chloro-5-phenyll H-l,5-benzodiazepine2,4-[ 3H,5H]-dion e and o-methyl-benzoyl chloride.

CH Cl from 7-chloro-5-phenyl-lH-l,5-benzodiazepine-2,4-( 3H ,5 H l-dioneand lauroyl chloride.

EXAMPLE 33 from '7-chloro-5-phenyll H-l ,5-benzodiazepine-2,4-[

' 3H,5H]-dione and palmitic acid chloride.

The compounds embraced by Formula 1 above have useful pharmacodynamicproperties. More particu larly, they exhibit psychosedative(tranquilizing), muscle-relaxing and anticonvulsive activities and verylow toxicity in warm-blooded animals, such as mice, rats, cats, rabbits,and dogs.

The phychosedative (tranquilizing) activity and the median lethal doseof the compounds embraced by Formula I were ascertained by standardpharmacological tests on mice.

The tranquilizing activity was ascertained by means of the slide test,in which the treated test animals are placed on a smooth metal platewhich is inclined at an angle of from the horizontal. The medianeffective tranquilizing dose (ED is that close which causes 50 percentof the test animals to slide off the plate due to the psychosedativeeffect of the test compound.

The median lethal dose (LD was determined by the method of Litchfieldand Wilcoxon, J. 'Pharmacol. exptl. T herap., Vol. 96, pg. 99 (1949).

The following table shows the average values obtained from these testsfor a representative number of compounds of the class defined by formulaI, as well as TABLE Slidetest LD mgm/kg Therap. Index LD ED Compounddiazepine-2,4-[ 3H,5H dione 7-Chloro-5-phenyll propionyll "-1,S-benzodiazenpine-2,4- [3H,5Hl-dione l l-Benzoyl-7-bromo-5- phenyl-l H-l ,S-benzodiazepine-2,4-[ 3H,5H l-dione 7-Chlorol cinnamoyl-S- phenyl-lH- I ,S-benzodiazepine-2,4-( 3 H ,5 H l-dione 7-Chloro-Z-methyl-benzoyl)-5-phenyll H- l ,5-

benzodiazepine-2,4-[ 3H, 5H1-dione 7-Chlorol -formyl5- phenyll H- l,S-benwdiazepine-2,4-[ 3H,5H] dione 7-Chlorol 3,4-dimethoxy-bcnzoyU-S-phenyl'-l H-] ,5-

benzodiazepine- 2,4-l 3H,5H l-dione 7-Chlorol-cycl0hexylcarbonyl-S-phenyh l H- l,5-benzodiazepine-2,4- [3H,SHl-dione6 7-Chloro-5-phenyll -phen- 3627 45 3 7-Chlorol -chloroacetyl- S-phenyllH- l ,S-benzodiazepine-2,4-[3H,5H]-dione 7-Chlorol -(4-nitro-benzoyl)-5-phenyll H-l ,5-benzodiazepine-2,4-[ 3H,5H dione 9l-Acelyl-7-chloro-5-phen- 7-Chlorol-(4-methyl-benzoyl)-5phenyll H-1 ,5benzodiazepine-2,4-[3H,SH]- dione7-Chloro-l-(2,4-dichlorobenZOyD-S-phenyI-IH-I,5- benzodiazepine-2,4-[3H,5H dione 7-Chloro-l-(2-fluoro-benzoyl )-5-phenyll H- l,S-benzodiazepine-2.4-[ 3H,5 H dione 7-Chlorol -furanoyl-5-phenyll H- l,5-benzodiazepine2,4- [3H,5H I-dione 7-Chloro-5-phenyl-l-thenoyllH-l,S-benzodiazepine-2,4- [3H,5Hl-dione For pharmaceutical purposes thecompounds according to the present invention are administered towarm-blooded'animals perorally or by the rectal route as activeingredients in customary dosage unit compositions, that is, compositionsin dosage unit form consistingessentially of an inert solidpharmaceutical carrier and one effective dosage unit of the activeingredient, such as tablets, coated pills, capsules, wafers, powders,suppositories and the like. One effective dosage unitof the compoundsaccording to the present invention is from 0.0166 to 0.84 mgm/kg bodyweight, preferably 0.083 to 0.42 mgm/kg body weight. The daily dose isfrom 0.166 to 2.5 mgm/kg.

The following examples illustrate a few dosage unit compositionscomprising a compound of the Formula I as an active ingredient andrepresent the best mode contemplated of putting the invention topractical use. The parts are parts by weight unless otherwise specified.

EXAMPLE 34 Tablets The tablet composition was compounded from thefollowing ingredients:

benzodiazepine-2,4-[ 3H,5Hl-dione 10 parts Lactose 33 parts Corn starch30 parts Colloidal silicic acid 1 part Magnesium stearate l part Total75 parts Compounding procedure:

a. The benzodiazepinedione compound was homogeneously stirred into awarmed fatty substance, such as polyethylene glycol or stearic acid, theresulting mixture was allowed to cool and solidify, and the solid masswas comminuted.

b. The lactose, the corn starch and the colloidal silicic acid werethoroughly admixed with each other, the mixture was granulated with theaid of a soluble starch paste, the comminuted benzodiazepinedione-fatmixture obtained in (a) and the magnesium stearate were admixed with thegranulate, and the composition was compressed into 75 mgm tablets. Eachtablet contained 10 mgm of the benzodiazepinedione compound and, whenadministered perorally to a warm-blooded animal of about 60 kg bodyweight in need of such treatment, produced very good psychosedative,muscle-relaxing and anticonvulsive effects.

The same results were obtained when 7-chlorol -cinnamoyl-S-phenyll H-l,5-benzodiazepine-2,4-[3H,5 H]-dione or7-chloro-5-phenyl-l-propionyl-lH-l,5- benzodiazepine-2,4-[3H,5H1-dionewas substituted for 1-benzoyl-7-chloro-5-phenyll H- l ,S-benzodiazepine-2,4-[3H,5H]-dione in the above tablet composition.

EXAMPLE 35 Coated pills The pill core composition was compounded fromthe following ingredients:

benzodiazepine-2,4-[3H,5Hl-dione 5.0 parts Lactose 28.5 parts cornstarch l5.0 parts Gelatin 1.0 part Magnesium stearatc 0.5 part Total50.0 parts Compounding procedure:

A comminuted mixture of the benzodiazepinedione compound and a fattysubstance, as described in Example 35(a), was prepared and the same wasintimately admixed with the lactose and the corn starch. The resultingmixture was moistened with an aqueous 10 percent solution of thegelatin, the moist mass was forced through a 1 mm mesh screen and theresulting granulate was dried at 40 C and again passed through thescreen. The dry granulate was uniformly admixed with the magnesiumstearate, and the resulting composition was compressed into 50 mgm pillcores, which were then coated with a thin shell consisting essentiallyofa mixture of sugar, titanium dioxide, talcum and gum arabic, and thecoated pills were polished with beeswax. Each pill contained 5 mgm ofthe benzodiazepinedione compound and, when .administered perorally to awarm-blooded animal of about 60 kg body weight in need of suchtreatment, produced very good psychosedative, muscle-relaxing andanticonvulsive effects.

The same results were obtained when one of the following compounds wassubstituted for the benzodiazepinedione compound in the above pill corecomposition:

a. 7-chloro-5-phenyll -propionyll H-l ,5-benzodiazepine-2,4-[3H,5H1-dione;

b. 7-chlorol -cinnamoyl-5-phenyll H-l ,5-benzodiazepine-2,4-[3H,5Hl-dione;

c. 7-chloro-l-(3',4'-dimethoxy-benzoyl)-5-phenyll H-l,5-benzodiazepine-2,4-[3H,5H1-dione; or

d. 1-benzoyl-7-bromo-5-phenyl- 1 PL] ,5- benzodiazepine-2,4-[3H,5H]-dione.

EXAMPLE 36 l-Benzoyl-7-chloro-S-phenyll H- l ,5-

benzodiazepine-2,4-[ 3H,5H l-dione l0.0 pans Corn starch l90.0 pansTotal 200.0 pans Compounding procedure:

A comminuted mixture of the benzodiazepinedione compound and a fattysubstance, as described in Example 35(a), was prepared and the same wasintimately admixed with the corn starch, and 200 mgm portions of theresulting mixture were filled into gelatin capsules of suitable size.Each capsule contained 10 mgm of the benzodiazepinedione compound and,when administered perorally to a warm-blooded animal of about 60 kg bodyweight in need of such treatment, produced very good psychosedative,muscle-relaxant and anticonvulsive effects.

The same results were obtained when 7-chloro-5- phenyll -propionyll H-l,5-benzodiazepine-2,4-[ 3H ,5. Hl-dione or7-chloro-l-formyl-S-phenyl-lH-l,5- benzodiazepine-2,4-[3H,5H1-dione wassubstituted for the benzodiazepinedione compound in the above capsulefiller composition.

EXAMPLE 37 Sustained release pills The pill core composition wascompounded from the following ingredients:

l-Benzoyl-7-chloro-5 -phenyl-l H- l ,5-

Compounding procedure:

The benzodiazepinedione compound, the carboxymethyl cellulose and thestearic acid were intimately admixed with each other, the resultingmixture was moistened with a solution of the cellulose acetate phthalatein 200 ml of a mixture of ethanol and ethyl acetate, the moist mass wasforced through a 1.5 mmmesh screen, the resulting granulate was dried at40C, and the dry granulate was compressed into 380 mgm pill cores whichwere subsequently coated with a thin shell consisting essentially of amixture of sugar and polyvinylpyrrolidone. Each pill contained 20 mgm ofthe benzodiazepinedione compound and, when administered perorally to awarm-blooded animal of about 60 kg body weight in need of suchtreatment, produced very good psychosedative, muscle-relaxing andanticonvulsive effects.

The same results were obtained when 7-chloro- Sphenyll -propionyl-l H-l,5-benzodiazepine-2,4- [3H,5]-dione or 7-chloro-I-cinnamoyI-SphenyI-IH-l,5-benzodiazepine-2,4-[3H,5H1-dionewas substituted for thebenzodiazepinedione compound in the above sustained release pill corecomposition..

EXAMPLE 38 Suppositories The suppository composition was compounded fromthe following ingredients: -(1-Benzoyl-7-chloro-5-phenyl-1H-l,5

benzodiazepine-2,4-[ 3H,5H1-dione 5.0 parts Suppository base (cocoabutter or mixture of triglycerides) l695.0 parts Total 1700.0 partsCompoundingprocedure:

The benzodiazepinedione compound was finely pulverized and thenuniformly blended with an immersion homogenizer into the suppositorybase which had previously been melted and cooled to 40C. 1,700 mgmportions of the resulting composition were poured at 35C into cooledsuppository molds. Each suppository contained 5 mgm of thebenzodiazepinedione compound and, when administered by the rectal routeto a warm-blooded animal of about 60 kg body weight in need of suchtreatment, produced very good psychosedative, muscle-relaxing andanticonvulsive effects.

The same results were obtained when 7-chloro-l-cinnamoyl-S-phenyll H-l,5-benzodiazepine-2,4-[ 3H,5 H]-dione or 7-chloro-5-phenyll -propionyl-1 H l ,5- benzodiazepine-2,4-[ 3H,5H ]-dione was substituted for thebenzodiazepinedione compound in the above suppository composition.

Analogous results were obtained when an equal amount of7-chloro-l-cyclohexylcarbonyl-5-phenyllH-l,5-benzodiazepine-2,4-[3H,5H1-dione,7-chlorol -chloroacetyl-5-phenyl-l H-l ,5-benzodiazepine-2,4-[3H,5l-l1-dione, 1 7-chlorol -lauroyl-5-phenyll H-l,S-benzodiazepine- [3H,5BV1-dione, 7-chloro-l-phenylacetyl-5-phenyl-lH-l,5- benzodiazepine-2,4-[3H,5H1-dione, or any one of the other compoundsembraced by Formula l above was substituted for the particularbenzodiazepinedione compounds in Example 34 through 38. Likewise, theamount of active ingredient in these examples may be varied to achievethe dosage unit range set forth above, and the amounts and nature of theinert pharmaceutical carrier ingredients may be varied to meetparticular requirements.

While the present invention has been illustrated with the aid of certainspecific embodiments thereof, it will be readily apparent to othersskilled in the art that the invention is not limited to these particularembodiments, and that various changes and modifications may i u s Ra 7-/3CH: 6 5 4 N--C wherein R is hydrogen, straight-chain alkyl of one to15 carbon atoms, chloromethyl, trifluoromethyl, methylamino, ethoxy,cyclohexyl, phenyl,

chlorophenyl, dichlorophenyl, tolyl, dimethoxyphenyl, nitrophenyl,benzyl, styry], thienyl or furyl,

R is hydrogen, methyl, chlorine or methoxy, and

R is hydrogen, 7-chloro- 7-bromo-, 8-methyl, 7-

trifluoromethyl or 8-trifluoromethyl.

2. A composition according to claim 1, wherein said compound isl-benzoyl-7-chloro-5-phenyll H-l ,5- benzodiazepine-2,4-[ 3H,5H ]-dione.

3. A composition according to claim 1, wherein said compound is7-chloro-l-cinnamoyl-5-phenyll H-l ,5-benzodiaZepine-2,4-[3H,5l-l1-dione.

4. A composition according to claim 1, wherein said compound is7-chloro-5-phenyl-l-propionyl-lH-l,5- benzodiazepine-2,4-[3H,5H1-dione.

5. A composition according to claim 1, wherein said compound is7-chloro-l-(3',4'-dimethoxy-benzoyl) 5- phenyll H-l,5-benzodiazepine-2,4-[ 3H,5H 1-dione.

6. The method of inducing psychosedation, relaxing the muscles andsuppressing convulsions in a warmblooded animal in need of suchtreatment, which comprises perorally or rectally administering to saidanimal an effective psychosedative, muscle-relaxing and anticonvulsiveamount of a compound of the formula be made without departing from thespirit of the invenwherein tion or the scope of the appended claims.

We claim:

1. A pharmaceutical dosage unit composition consisting essentially of asolid inert pharmaceutical carrier and an effective psychosedative,muscle-relaxing and anti-convulsive amount of a compound of the formulaR, is hydrogen, straight-chain alkyl of one to 15 carbon atoms,chloromethyl, trifluoromethyl, methylamino, ethoxy, cyclohexyl, phenyl,chlorophenyl, dichlorophenyl, tolyl, dimethoxyphenyl, nitrophenyl,benzyl, styryl, thienyl or furyl,

R is hydrogen, methyl, chlorine or methoxy, and

R; is hydrogen, 7-chloro-, 7-bromo-, 8-methyl, 7-

7. The method according to claim 6, wherein said compound isl-benzoyl-7-chloro-5-phenyl-lH-l,5- bcnzodiazcpinc-2,4-[3H,5Hl-dione.

8. The method according to claim 6, wherein said compound is7-chl0ro-l-cinnamoyl-5-phenyl-lH-l,5-

2. A composition according to claim 1, wherein said compound is 1-benzoyl-7-chloro-5-phenyl-1H-1,5-benzodiazepine-2,4-(3H,5H)-dione.
 3. A composition according to claim 1, wherein said compound is 7-chloro-1-cinnamoyl-5-phenyl-1H-1,5-benzodiazepine-2,4-(3H,5H)-dione.
 4. A composition according to claim 1, wherein said compound is 7-chloro-5-phenyl-1-propionyl-1H-1,5-benzodiazepine-2,4-(3H,5H)-dione.
 5. A composition according to claim 1, wherein said compound is 7-chloro-1-(3'',4''-dimethoxy-benzoyl)-5-phenyl-1H-1,5-benzodiazepine-2,4 -(3H,5H)-dione.
 6. The method of inducing psychosedation, relaxing the muscles and suppressing convulsions in a warm-blooded animal in need of such treatment, which comprises perorally or rectally administering to said animal an effective psychosedative, muscle-relaxing and anticonvulsive amount of a compound of the formula
 7. The method according to claim 6, wherein said compound is 1-benzoyl-7-chloro-5-phenyl-1H-1,5-benzodiazepine-2,4-(3H,5H)-dione.
 8. The method according to claim 6, wherein said compound is 7-chloro-1-cinnamoyl-5-phenyl-1H-1,5-benzodiazepine-2,4-(3H,5H)-dione.
 9. The method according to claim 6, wherein said compound is 7-chloro-5-phenyl-1-propionyl-1H-1,5-benzodiazapine-2,4-(3H,5H)-dione.
 10. The method according to claim 6, wherein said compound is 7-chloro-1-(3'' ,4''-dimethoxy-benzoyl)-5-phenyl-1H-1,5-benzodiazepine-2,4-(3H,5H)-dione. 